This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Structure-function relationships of nucleic acids, such as that of tRNA in protein synthesis, are fundamental to all cell and molecular biology. In order to probe the structure-function relationships of RNAs as potential targets or tools, we have developed methods for the introduction of native, non-natural, and stable isotope labeled nucleosides. We have found that modified nucleosides in tRNA play an important structural and functional role both within the tRNA molecules and in tRNA anticodon recognition of select codons at the wobble position. Modified nucleosides alter codon "wobble", enhance ribosome binding, explain programmed translational frameshifting, are determinants for aminoacyl-tRNA synthetase recognition, and are involved in human immunodeficiency virus selection of a specific human tRNA to prime reverse transcription.